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In research results published in the November 20 issue of Science Translational Medicine, investigators from Massachusetts General Hospital, Harvard Medical School, the Harvard School of Public Health, and the University of Iowa showed that even low levels of the Alzheimer's disease (AD) APOE4 protein can increase the number and density of amyloid beta (A-beta) brain plaques, neuronal damage, and the amount of toxic-soluble A-beta within the brains of mice that serve as models of the human disease.

AD is the most frequent age-related neurodegenerative disorder and a major public health concern. The presence of the apolipoprotein E-e4 (APOE4) allele is, scientists say, is the most significant genetic risk factor for disease development.

The presence of one APOE4 copy substantially increases the risk of developing the disease by a factor of three compared with the most common APOE3 allele, whereas two copies lead to a 12-fold increase. While one in four people carry the APOE4 gene, it occurs in 65% to 80% of all people who develop AD.

The APOE4 protein has also been implicated in other neurological conditions including Parkinson’s disease and multiple sclerosis, and is associated with poor clinical outcome in patients with traumatic brain injury.

To better define the role of APOE proteins in AD, the researchers infused genes for each form of APOE (APOE1, APOE2, APOE3, and APOE4) directly into the brains of adult mice. They found that each variant changed the course of Alzheimer’s progression, even after characteristic hallmarks of the disease (like the buildup of amyloid plaques) were already present.

Introduction of the APOE4 gene worsened amyloid plaque development and damage to neurons, while mice injected with the APOE2 gene exhibited a decreased amount of plaque development and less neuronal damage. The results help clarify why people carrying APOE4 are at high risk for developing Alzheimer’s, while individuals harboring the rare APOE2 gene appear to be protected from disease. Therapies aimed at reducing levels of APOE4 and boosting concentrations of APOE2 could potentially benefit Alzheimer’s patients, the authors suggest.

The study results, the authors say, demonstrate a clear effect of APOE isoforms on neurotoxicity assessed by synapse loss and neuritic dystrophies, both likely related to impairment of neuronal system function.

Importantly, these research results provide evidence that at least in animal models, APOE2 has a gain-of-function effect and can reverse established amyloid body (Ab) deposits, as well as support synaptic and neuritic plasticity. This could explain the decade-long difference in age of onset between patients who inherit APOE4 versus APOE2 alleles, reflecting both a different initiation point and continuous differences in the kinetics of Ab deposition and clearance, as well as allele-specific differences in the extent of neurotoxicity associated with the deposits. This dual function of APOE2 may lead to therapeutic approaches aimed at mimicking its plaque-clearing and synaptic restoration capacity.

“This study has allowed us to sort out, in mice, which effects of the different types of APOE were most important to variation in amyloid plaque deposition,” says Eloise Hudry, Ph.D., of MGH-MIND, lead author of the Science Translational Medicine report (titled “Gene Transfer of Human Apoe Isoforms Results in Differential Modulation of Amyloid Deposition and Neurotoxicity in Mouse Brain”). “Our results imply that APOE-based therapeutic approaches may help to alleviate the progression of Alzheimer's disease. More study is needed to pursue that possibility and to investigate the potential use of this gene transfer technology to introduce other protective proteins into the brain.”

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